Vaccines are widely used for preventing diseases such as infectious diseases. A vaccine is a biological formulation comprising an antigen which produces an immune response in a living organism. It prevents infection by a specific disease agent by inoculation with an inactivated or attenuated antigen into an animal such as human so as to induce immunity against a specific disease.
Vaccines can be broadly grouped as: live vaccines, inactivated vaccines, a toxoids and the like. A live vaccine refers to an attenuated vaccine produced by attenuating toxicity and virulence of a pathogen. The vaccine can multiply in the body of an inoculated animal. An inactivated vaccine refers to a vaccine prepared from a pathogen treated with formalin, ultraviolet radiation and the like to abolish its infectivity, toxicity and virulence, or from a component thereof. The vaccine will not multiply in the body of an inoculated animal. A toxoid is a class of inactivated vaccines, which is prepared by removing toxins from bacterium to abolish its toxicity and leaving only its immunogenicity intact.
In general, live vaccines can induce a good immune response in many cases while they have higher risks of toxicity than inactivated vaccines. In contrast, inactivated vaccines and the like are safer than live vaccines while immunogenicity of inactivated vaccines is often too weak to achieve sufficient immune effects by single administration. Therefore, inactivated vaccines may be administered in repeated doses or in combination with an adjuvant to achieve sufficient immune effects.
An adjuvant refers to a substance which enhances an immune response against an antigen by administering it in combination with that antigen to a living organism. By adding an adjuvant to an inactivated vaccine and the like, immune effects can be enhanced and duration of effective immunity can be extended. The dose and frequency of administration of a vaccine can be reduced, which in turn results in decreasing its production volume.
Best known adjuvants include Complete Freund's adjuvant and Incomplete Freund's adjuvant. Complete Freund's adjuvant is a mixture of liquid paraffin, surfactant and cells of Tubercle Bacillus while Incomplete Freund's adjuvant is a mixture of liquid paraffin and surfactant. These adjuvants are commonly used for laboratory animals, but they are used neither for human nor for animals because they show a strong local response at a site of inoculation. In addition, precipitated adjuvants such as aluminium hydroxide (alum) and sodium hydroxide, oily adjuvants such as liquid paraffin, sterilized microorganism and the like are known. Note that only an aluminium hydroxide gel is currently approved for human use.
In the case of trans-mucosal infections such as respiratory infection, vaccination via injection often fails to effectively induce immunity at a site of infection (a surface of mucous membrane). In contrast, a mucosal vaccine attracts attention as a means for reliably and efficiently raising an immune response at a surface of mucous membrane. A mucosal vaccine is a vaccine in which an antigen is directly administered to a surface of mucous membrane in order to activate an immune system present at a surface of mucous membrane.
In the immune system of the mucous membrane, not only are the responses due to IgG antibody of the systemic immune system but also to secretory IgA antibody, cytotoxic T-cells, delayed allergic reaction mediated Th1 cells and the like, which are involved in the defense mechanism. Among these, it is suggested that secretory IgA functions to neutralize a pathogen by secretion at the mucous membrane, and plays a significant role in resistance against a pathogen of trans-mucosal infection. Therefore, a mucosal vaccine is expected to achieve more effective immune effect against trans-mucosal infection than a common injectable vaccine.
However, in the case of a mucosal vaccine, administration of an antigen alone to mucous membrane often cannot induce sufficient immunity since a surface of mucous membrane is always exposed to invasion of foreign objects. Therefore, a mucosal vaccine should be used in combination with a highly efficacious adjuvant for mucosal immunity (a mucosal adjuvant). In human beings, cholera toxins, E. coli heat-labile toxins and the like have been tried as mucosal adjuvants.
Trans-mucosal infections in canine include, for example, canine infectious tracheobronchitis (Kennel Cough), canine distemper, canine parvovirus infection, canine coronavirus infection and canine herpesvirus infection. The canine infectious tracheobronchitis is a disease showing dry cough, nasal discharge, fever and the like as main symptoms. Its main pathogens include canine adenovirus type 2, canine parainfluenza virus and Bordetella bronchiseptica (scientific name “Bordetella bronchiseptica,” hereinafter), and in addition, canine adenovirus type 1, canine herpesvirus, reovirus, pneumovirus and the like also cause this disease.
Trans-mucosal infections in feline include, for example, feline infectious tracheobronchitis, feline panleukopenia, feline infectious peritonitis/feline intestinal coronavirus infection, feline leukemia, feline immunodeficiency virus infection. Feline infectious tracheobronchitis is a disease showing fever, nasal discharge, sneezing and the like as main symptoms. Its main pathogens are feline calicivirus and feline herpesvirus, and in addition, Chlamydophila felis (scientific name “Chlamydophila felis,” hereinafter), Bordetella bronchiseptica and the like also cause this disease.
In addition, there are various trans-mucosal infections in mink, rat, guinea pig, rabbit, ferret, mouse and the like.
For vaccines against canine respiratory infection, for example, live or inactivated vaccines of canine parvovirus, mixed live or inactivated vaccines of canine distemper, canine adenovirus, canine parainfluenza virus, canine coronavirus and the like have been used, respectively. Further, for vaccines against feline respiratory infection, for example, mixed live vaccines of feline viral rhinotracheitis, feline calicivirus, feline panleukopenia, aluminium-gel-adjuvant-added inactivated vaccines, oily-adjuvant-added inactivated vaccines and the like have been used.
Bordetella bronchiseptica, which is a gram-negative obligate aerobic bacillus, is a pathogenic bacterium of swine atrophic rhinitis and Bordetella bronchiseptica disease in rat, guinea pig, rabbit, ferret, feline, canine, swine, monkey and the like. As described above, it is also one of the pathogenic bacteria of canine infectious tracheobronchitis and feline infectious tracheobronchitis. Note that other Bordetella bacteria include Bordetella pertussis (scientific name “Bordetella pertussis”) and a pathogenic bacterium of Meleagris gallopavo coryza (scientific name “Bordetella avium”).
For vaccines against swine atrophic rhinitis, for example, inactivated vaccines of swine Bordetella infection, purified inactivated vaccines, oily-adjuvant-added mixed inactivated vaccines with swine pasteurellosis, mixed toxoids with Pasteurella multocida and the like have been used.
For example, Patent Document 1 (see below) describes a mixed toxoid which is effective for preventing swine atrophic rhinitis, the toxoid comprising a necrotoxic toxoid produced by Bordetella and toxinogenic Pasteurella as a main ingredient.
Patent Document 2 describes a vaccine composition against Kennel Cough comprising Bordetella bronchiseptica p68 antigen. Patent Document 3 describes a canine polyvalent vaccine against Kennel Cough comprising one or more of canine distemper virus, canine adenovirus type 2, canine parainfluenza virus, canine coronavirus, canine parvovirus and leptospire; and Bordetella bronchiseptica p68 antigen. Patent Document 4 and 5 describe an immunoadjuvant comprising cells and cell components of Bordetella bronchiseptica from swine.    Patent Document 1: WO95/34322    Patent Document 2: WO2006/106424    Patent Document 3: WO2006/38115    Patent Document 4: Japanese Patent Laid-Open No. S58-83629    Patent Document 5: Japanese Patent Laid-Open No. S59-157029